Modulation of phagocyte activation by the synthetic oligopeptide fmet-leu-phe has been studied using membrane potential sensitive fluorescent probes, assays of chemotaxis, and chemoattractant receptors, superoxide generation and degranulation in neutrophils from normal subjects, patients with select defects of phagocyte function and the use of certain pharmacologic probes. The data indicate modulation of fmet-leu-phe receptor affinity, through either negative cooperativity or changing populations of heterogenous receptors may be an important mechanism by which neutrophils adapt and respond to a gradient of chemoattractant during the process of chemotaxis. Related studies of two populations of neutrophils we described previously have revealed heterogeneity of fmet-leu-phe binding among neutrophils. Cells that respond to fmet-leu-phe with a membrane depolarization have more chemoattractant associated with them than cells which either do not respond or show a hyperpolarization. Thus, receptor studies of neutrophil suspensions need to be refined to consider heterogeneity among neutrophils. In other studies histamine was found to inhibit superoxide production by fmet-leu-phe but not by calcium ionophore A23187 or phorbol myristate acetate. This inhibition was prevented by cimetidine. Thus, pharmacologic manipulation of receptor function is possible in the future.